IL-17-producing Th17 cells are now considered to be the most potent effector T cell for inducing tissue inflammation in both experimental autoimmune disease models and in humans. Th17 cells produce IL-17A, IL-17F, IL-21 and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors on parenchymal tissues. Our laboratory was among the first to identify differentiation factors for Th17 cells. We showed that TGF-beta plus IL-6 or IL-21 together induces differentiation and amplification of Th17 differentiation but IL-23 stabilizes their development and evokes pathogenic phenotype in differentiating Th17 cells. By undertaking a high-density temporal transcriptomic analysis, in collaboration with the investigators at the Broad Institute, our laboratory was first to develop a regulatory network for the development of Th17 cells. Our laboratory also identified pathogenic and nonpathogenic Th17 cells that may have different functions in inducing inflammation vs. tissue homeostasis. Elucidation of the effects of these different Th17 cell subsets on disease is a major research effort in the laboratory.
Type I regulatory T (Tr1) cells are FoxP3- CD4+ T cells with strong immunosuppressive properties that were identified in various tissues during autoimmune inflammation. They are critical for the maintenance of tolerance, produce large amounts of IL-10, and have unique transcription factor requirements. Our laboratory was among the first to identify IL-27 as a differentiation factor for in vitro generation of Tr1 cells. We are currently applying cutting-edge methods to build the regulatory network that drives the differentiation of this T cell subset.
Co-inhibitory receptors, also called ‘check-point’ receptors, have received considerable attention as blockade of these receptors, such as PD-1 and CTLA-4, has proven to be an effective immunotherapeutic strategy against cancer. In chronic viral infections and cancer, the sustained expression of co-inhibitory receptors on CD8+ T cells is associated with dysfunctional or “exhausted” phenotype. Moreover, the accumulation of co-inhibitory-receptors on CD8 T cells correlates with increased dysfunction. Although co-inhibitory receptors clearly have a role in T cell dysfunction, how these co-inhibitory molecules are induced on effector T cells is not known. In addition to chronic viral infections and cancer, dysregulation of co-inhibitory pathways is also implicated in the pathogenesis of autoimmune diseases such as multiple sclerosis.
T cell immunoglobulin and mucin domain-containing 3 (Tim-3) was first identified in our laboratory and is a co-inhibitory receptor that is specifically expressed on differentiated interferon (IFNgamma)-producing CD4+ and CD8+ T cells, and induces their death and dysfunction. Recently, Tim-3 expression has been shown to mark the most severely “exhausted” or dysfunctional T cells that arise in chronic viral infections, such as HIV and HCV, as well as in cancer. Largely stemming from our work on Tim-3, agents that interfere with Tim-3 signaling are now in clinical trials for cancer. Currently, we are studying the pathways that drive expression of Tim-3 and the biochemical pathways by which Tim-3 mediates its effects in T cells.
T cell immunoreceptor with Immunoglobulin and ITIM domains (TIGIT) is a co-inhibitory receptor expressed on activated CD4+, CD8+, and NK T cells, which binds to two ligands, CD155 and CD112, expressed on antigen presenting cells. The laboratory has been working on the mechanisms by which TIGIT mediates inhibition of T cell responses. In addition to inducing IL-10+ DCs, we showed that TIGIT also has cell intrinsic inhibitory effects. TIGIT also directs the suppressor function of Foxp3+Tregs towards Th1 and Th17 cells while sparing Th2 cells from Treg mediated inhibition. Currently, we are investigating how the expression of each of these molecules is regulated and how they each achieve their inhibitory effects in T cells. We are further identifying new inhibitory receptors on T cells using systems biology approaches.
Tim-1 is a transmembrane glycoprotein identified as a member of the Tim family of genes that regulates immune responses. In the immune system, Tim-1 has been shown to be expressed on various immune cell populations. Currently, we are studying how Tim-1 regulates the function and responses of a novel B cell population that exhibits regulatory properties, regulatory B cells, Breg.
Autoimmune Disease Model: The laboratory has generated numerous models that recapitulate for the study of multiple sclerosis. The laboratory generated a TcR transgenic mouse that harbors reactivity to myelin proteolipid protein (PLP) and differentially develops disease on different genetic backgrounds. The 2D2 TcR transgenic mouse that harbors reactivity against myelin oligodendrocyte glycoprotein (MOG) is the “gold standard” in the field of CNS autoimmunity. The 1C6 TcR transgenic mouse is the only model that recapitulates the transition of relapsing-remitting disease to chronic progressive disease that is observed in MS patients. These models are widely used in the laboratory and in the field as tools to facilitate studies of immune mechanisms of autoimmune disease pathogenesis.
Autoimmune Disease Model: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system that is distinct from Multiple Sclerosis (MS) and is characterized by severe attacks of optic neuritis and myelitis in the spinal cord. The presence of serum autoantibody specific for the aquaporin-4 (AQP4) water channel is a powerful diagnostic marker for NMO. Thus, the role of APQ-4 autoantibodies in disease is an area of active research. AQP4-specific autoantibodies may play a pivotal role in the pathogenesis of NMO. However, immunization with AQP4 protein to induce NMO-like disease has met with limited success in recapitulating the disease in animal models. Since AQP4 is considered to be the primary autoantigen in NMO, this raises the important question of whether AQP4-specific T cell: B cell collaboration would result in the development of NMO-like disease, and whether AQP4-specific B cells induce AQP4-specific T cells to differentiate into pathogenic effector T cells and drive development of NMO-like disease. To address these questions we are developing genetically engineered models harboring both antibodies and T cell receptors specific for AQP4 to understand their contribution to the pathogenesis of NMO. This project is supported in part by The Guthy-Jackson Charitable Foundation.
Innate lymphoid cells (ILCs) are a population of cells that preferentially reside at mucosal tissues, such as the lung and the intestine, and rapidly produce effector cytokines in response to epithelial cell stress or injury. ILCs can be divided into subsets reminiscent of those described for CD4 T cells, including IL-5 producing ILC2 and IL-17 producing ILC3. ILCs have been shown to play both protective and pathogenic roles during mucosal tissue inflammation, but the molecular signals that modulate these dichotomous responses are unclear. As part of a collaborative project with Dr. Aviv Regev’s lab and the Food Allergy Scientitifc Initiative at the Broad Institute, we are utilizing single cell genomics to identify novel regulators of ILC function in homeostatic and inflammatory settings.
Using Multiple Sclerosis patient-specific induced pluripotent stem (iPS) cells to develop a better understanding of disease pathology and to develop novel therapies. We have generated various iPS cell lines from patients with either relapsing-remitting or progressive Multiple Sclerosis by using a Sendai virus based reprogramming system that leaves the genome of the iPS cells un-modified, a very important consideration for potential therapeutic application. We are using these iPS cell lines to derive cell types that are lost during the course of disease, including oligodendrocytes and neuronal cell types. In addition, we are focusing on differentiation of T cells from patient-specific iPS cells. The long-term goal is to differentiate these T cells into regulatory cells. We are further using the CRISPR/Cas system to engineer the human iPS cell lines to generate reporter lines that facilitate their directed differentiation. Our studies are performed in a state-of-the-art facility that allows the culture and genetic manipulation of human iPS cells and the molecular, cellular, and functional analysis of their derivatives. Our research willprovide a deeper understanding of disease pathology and will contribute to the development of novel therapies for MS.